The major objective of the proposed investigation is to gain an understanding of the biochemical basis for the action of glucocorticoids. Two classes of target tissues which show significantly different physiological responses to treatment with the glucocorticoids are currently under investigation in this laboratory. These are: (1) lymphoid tissues such as rat and mouse thymus and the cortisol-sensitive and -resistant lines of mouse lymphosarcoma which are being used as a model system to investigate the biochemical changes produced by cortisol that may be of significance in mediating the regression and dissolution of lymphoid tissues, and (2) rat liver; in which the basis for the action of glucocorticoids on the induction of specific enzymes is being studied. This proposal focuses attention on the significance of the intracellular binding of glucocorticoids to specific macromolecules ("receptors") in lymphoid tissues and liver. The primary objectives of this work are: (1) to determine the intracellular distribution and certain physiochemical properties of the glucocorticoid-receptor complex; (2) to provide evidence that the steroid-receptor complex is the active entity which mediates the physiological and pharmacological effects produced by glucocorticoids; (3) to gain information on the manner in which the glucocorticoid-receptor complex may influence DNA biosynthesis; (4) to stimulate the development of new compounds and determine the mechanism by which antihormones (steroid analogs) act in target tissues; (5) to study the basis for the resistance of tumors to glucocorticoids of their dependency on these steroids; and (6) to use this information to explain the basis of action of glucocorticoids as well as to improve therapy with these hormones and advance the use of antihormones. BIBLIOGRAPHIC REFERENCES: Mayer, M., and Rosen, F. Myofibrillar Protease Activity in Rats Bearing Walker Carcinoma 256. Proc. Am. Assoc. Cancer Research 16: 97, 1975. Higby, D., Gailani, S., Nussbaum, A., McHugh, M., and Rosen, F. Correlation of Glucocorticoid Receptors to the In Vitro Effects of Cortisol on H3-Uridine (H3-U) Incorporation into RNA in Human Neoplastic Hematopoietic Cells. Clinical Research 23:339A. 1975.